Stabilized liquid fosaprepitant formulations

ABSTRACT

The present invention relates to stable pharmaceutical compositions of fosaprepitant or a salt thereof in the form of ready-to-use or ready-to-dilute compositions suitable for parenteral administration.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of Indian Application 4180/MUM/2015,filed on Nov. 3, 2015.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical liquid compositions ofthe neurokinin 1 (NK1) receptor antagonist fosaprepitant and relatedcompounds with enhanced stability against degradation.

BACKGROUND

Nausea and vomiting are common and feared symptoms among cancerpatients; up to 80% of patients experience chemotherapy-induced nauseaand vomiting (CINV) without prophylactic therapy. The syndrome may havea significant impact on the treatment and quality of life as patientsmay delay or even cancel scheduled chemotherapies. Generally, CINVsyndrome can be categorized as acute, delayed or anticipatory. In acuteCINV, nausea and vomiting appear within the first 24 hours afterchemotherapy, while in the case of delayed CINV, symptoms can last forseveral days. Anticipatory CINV is a conditional response that occurs inpatients who had poorly controlled CINV symptoms during a previouscourse of chemotherapy.

Until recently the prevention and treatment of CINV symptoms involvedthe use of corticosteroids, dopamine D2 antagonists and serotonin 5-HT3receptor antagonists. Therapies consisting of serotonin 5-HT3 receptors(such as Kytril® (granisetron), Zofran® (ondansetron), Anzemet®(dolesetron), Aloxi® (palonosetron) and Navoban® (Tropisetron)). Aloxi®(palonosetron), due to its longer half-life, is the only serotonin 5-HT3receptor antagonist currently approved for the prevention of both acuteand delayed CINV. Usually, a combination of Aloxi® and a corticosteroid,administrated prior to chemotherapy, followed by administration of oneor both agents for several days is used for the prevention of delayedCINV. However, unpleasant adverse-effects due to the multiple dosing of5-HT3 receptor antagonist during the treatment of delayed CINV symptoms,such as headache and constipation, led to the addition of neurokinin 1(NK1) receptor antagonists, such as Aprepitant or Fosaprepitant, in thetreatment regimen.

Aprepitant is a highly-selective antagonist of NK1 receptors with littleor no affinity for serotonin, dopamine or corticosteroid receptors. Itis available in the form of capsules for oral administration (Emend®)containing either 40 mg, 80 mg, or 125 mg of aprepitant. Unfortunately,oral capsule formulations are easy to swallow for patients undergoingchemotherapy or postoperative condition since such capsules themselvesoften induce nausea and vomiting.

Fosaprepitant is a water-soluble phosphorylated prodrug of aprepitant,which may be administered intravenously. Fosaprepitant has been reportedto undergo rapid conversion to aprepitant in less than 30 minutes afteran IV infusion.

Fosaprepitant Dimeglumine for Injection (Emend® for Injection) is soldas a lyophilized prodrug of aprepitant. To administer, a small about ofsaline is combined with the lyophilized powder, and then transferred toan infusion bag to yield a final concentration of 1 mg/ml. Care must betaken during the initial dilution to prevent foaming. The reconstitutedfinal drug solution is reported to be stable only for 24 hours atambient room temperature (at or below 25° C.) after reconstitution. Oneof the primary degradation products is aprepitant. As aprepitant isgenerated, it will precipitate from an aqueous solution. This poses achallenge in preparing ready-to-use or ready-to-dilute compositions ofFosaprepitant dimeglumine.

It is an object of the invention to provide a stable ready-to-use liquidcompositions of fosaprepitant suitable for parenteral administration. Itis an object of the invention to provide a stable ready-to-dilute liquidcompositions of fosaprepitant for parenteral administration. It is anobject of the invention to provide liquid compositions of fosaprepitantwhich do not degrade to aprepitant. It is an object of the invention toprovide a stable composition of fosaprepitant containing less than 10%w/v of aprepitant, even when stored over prolonged periods of time.

The details of one or more embodiments are set forth in the descriptionsbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Aprepitant Formation over time at 2-8° C. in fosaprepitantcompositions.

FIG. 2: Comparative pharmacokinetics of fosaprepitant compositions.

FIG. 3: Comparative Pharmacokinetics of fosaprepitant compositions.

DETAILED DESCRIPTION

Before the present methods and systems are disclosed and described, itis to be understood that the methods and systems are not limited tospecific synthetic methods, specific components, or to particularcompositions. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only andis not intended to be limiting.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Ranges may be expressed herein as from “about” oneparticular value, and/or to “about” another particular value. When sucha range is expressed, another embodiment includes

from the one particular value and/or to the other particular value.Similarly, when values are expressed as approximations, by use of theantecedent “about,” it will be understood that the particular valueforms another embodiment. It will be further understood that theendpoints of each of the ranges are significant both in relation to theother endpoint, and independently of the other endpoint.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not.

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.“Exemplary” means “an example of” and is not intended to convey anindication of a preferred or ideal embodiment. “Such as” is not used ina restrictive sense, but for explanatory purposes.

Disclosed are components that can be used to perform the disclosedmethods and systems. These and other components are disclosed herein,and it is understood that when combinations, subsets, interactions,groups, etc. of these components are disclosed that while specificreference of each various individual and collective combinations andpermutation of these may not be explicitly disclosed, each isspecifically contemplated and described herein, for all methods andsystems. This applies to all aspects of this application including, butnot limited to, steps in disclosed methods. Thus, if there are a varietyof additional steps that can be performed it is understood that each ofthese additional steps can be performed with any specific embodiment orcombination of embodiments of the disclosed methods.

The term “aprepitant” or “fosaprepitant” includes not only “aprepitant”or “fosaprepitant” per se but also its pharmaceutically acceptablederivatives such as pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, pharmaceutically acceptable hydrates,pharmaceutically acceptable anhydrates, pharmaceutically acceptableesters, pharmaceutically acceptable polymorphs, pharmaceuticallyacceptable tautomers, pharmaceutically acceptable complexes etc.Preferably, fosaprepitant is present in the form of dimeglumine salt.

The term “ready-to-use” refers to any liquid composition ofFosaprepitant, optionally comprising other pharmaceutically acceptableexcipients, in the form of a solution, suspension or emulsion whereinthe composition does not require any reconstitution or dilution withparenterally acceptable diluent and can be directly administered to thepatient.

The term “ready-to-dilute” or “concentrate ready for dilution” refers toany liquid composition of fosaprepitant, optionally comprising otherpharmaceutically acceptable excipients, in the form of a solution,suspension or emulsion in which the composition can be wherein furtherdiluted with a suitable solvent for parenteral administration beforeadministering to the patient.

The term “stable” refers to any composition of Fosaprepitant wherein noprecipitation of aprepitant is observed such that the compositionremains clear and has sufficient stability to allow storage at aconvenient temperature and relative humidity (RH), such as between about0° C. and about 60° C. and about 20% to 75% RH, for a reasonable periodof time, such as at least about one week, at least about one month, atleast about three months, at least about six months, at least about oneyear, or at least about 2 years. In contrast, commercially availableEmend® for Injection substantially degrades after dilution in this timeperiod. In certain embodiments, stabilized fosaprepitant formulationswill develop less than 10% w/v of aprepitant of the total compositionover a period of time. For instance, after a stabilized liquidformulation is stored at 2-8° C. for a period of at least 1 month, nomore than 10%, 5% or 2.5% aprepitant will be generated. In someembodiments, after a stabilized liquid formulation is stored at 2-8° C.for a period of at least six months, no more than 10%, 5% or 2.5%aprepitant will be generated. The said stable compositions ofFosaprepitant comprise not more than 10% w/v of aprepitant over thestorage period, either in free form or in the form bound to albumin. Ina preferred embodiment, the said stable compositions of Fosaprepitantcomprise not more than 5% w/v of aprepitant over the storage period,either in free form or in the form bound to albumin. In a more preferredembodiment, the said stable compositions of Fosaprepitant comprise notmore than 3% w/v of aprepitant over the storage period, either in freeform or in the form bound to albumin.

The ready-to-use compositions of fosaprepitant are stable in aqueousmedium/vehicle for at least 30 days with no aprepitant precipitation,for instance, as measured by visual inspection.

The term “parenteral” or “injectable” refers to routes selected fromsubcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal(ID), intraperitoneal (IP) and the like.

In an embodiment of the invention, the ready-to-use or ready-to-dilutecompositions may be formulated as aqueous or non-aqueous solutions,suspensions or emulsions.

The pharmaceutical compositions of the present invention comprise one ormore pharmaceutically acceptable liquid excipient(s) selected from, butare not limited to, solvents/co-solvents, surfactants, solubilizers,wetting agents, water immiscible solvents, water, water misciblesolvents, oily components, hydrophilic solvents, hydrophobic solvents,emulsifiers, preservatives, chelating agents, antioxidants, anti-foamingagents, buffering agents, pH adjusting agents, osmotic agents, channelforming agents, osmotic adjustment agents, and the like or mixturesthereof.

The pharmaceutical compositions of the present invention may furthercomprise one or more stabilizers.

The ready-to-use or ready-to-dilute compositions may be sterileinjectable solutions, suspensions or emulsions in a nontoxic,parenterally acceptable vehicle. Exemplary vehicles include, but are notlimited to, water for injection, isotonic dextrose solution, albuminsolution (5%, 10%, or 25%), Ringer's solution, and isotonic sodiumchloride solution.

Preferably, the vehicle comprises albumin solution (5%, 10%, or 25%).Suitable albumin solution that may be employed include, but are notlimited to, commercially available albumin preparations, such asAlbuminar® (Centeon/Aventis Behring), Buminate® (Baxter Laboratories),Plasbumin® (Bayer Biological), AlbuRx® (CSL Behring), Albutein® (AlphaTherapeutic), Albumin (Human) (Immuno-U.S.), Albumarc® (American RedCross), Human Serum Albumin (Swiss Red Cross) and the like. Thecommercially available albumin preparations comprise pharmaceuticallyacceptable excipient(s) such as sodium N-acetyltryptophanate, sodiumcaprylate, sodium chloride, sodium bicarbonate, sodium hydroxide, oracetic acid, and the like or mixtures thereof.

Alternatively, albumin solution can be prepared by mixing albumin powderin water along with other pharmaceutically acceptable excipient(s) asavailable in the commercially available albumin products. Albumin may benatural in origin or synthetically prepared.

Preferably, the ready-to-use or ready-to-dilute compositions willinclude a vehicle in an amount from about 0 ml to greater than or equalto 200 ml. Ready-to-dilute formulations typically have lower amounts ofvehicle, e.g., no more than 5 ml, no more than 10 ml or no more than 15ml. In some embodiments, the ready-to-dilute compositions does notcomprise any vehicle. Ready-to-use formulations, on the other hand, willtypically have higher amounts for vehicle. For instance, a ready-to-useformulation can include vehicle in an amount from 75-200 ml, 100-200 ml,100-150 ml

Suitable solubilizers that may be employed include, but are not limitedto, various solvents such alcohols (ethanol, octanol, glycofurol),various glycols (propylene glycol, polyethylene glycol, glycerol etc.),and aprotic solvents such as dimethylacetamide, Isopropyl myristate,dimethyl sulphoxide (DMSO), dimethyl isosorbide, methylene chloride,triacetin, diacetin, tributyrin, triethyl citrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylglycerides, triethylphosphate, diethyl phthalate, diethyl tartrate, mineral oil, polybutene,silicone fluid, ethyl lactate, N-methyl-2-pyrrolidone, 2-pyrrolidone,methyl acetate, ethyl acetate, methyl ethyl ketone, dimethyl formamide,tetrahydrofuran, caprolactam, and 1-dodecylazacyclo-heptan-2-one, andthe like or mixtures thereof.

Preferably, the ready-to-use or ready-to-dilute compositions comprisesolubilizers in an amount from about 0 to about 5 ml of the totalcomposition.

Suitable wetting agents or surfactants include, but are not limited to,amphoteric, non-ionic, cationic or anionic molecules. Suitablesurfactants include, but are not limited to, polysorbates, sodiumdodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide,docusate sodium, cetyl trimethyl ammonium bromide (CTAB),polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide,polyoxyl 10 lauryl ether, Brij® surfactants (polyoxyethylenevegetable-based fatty ethers derived from lauryl, cetyl, stearyl andoleyl alcohols), bile salts (such as sodium deoxycholate and sodiumcholate), polyoxyl castor oil, nonylphenol ethoxylate, cyclodextrins,lecithin, phospholipids (such as phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol,etc.), methylbenzethonium chloride, carboxylates, sulphonates, petroleumsulphonates, alkylbenzenesulphonates, naphthalenesulphonates, olefinsulphonates, alkyl sulphates, sulphates, sulphated natural oils andfats, sulphated esters, sulphated alkanolamides, alkylphenols(ethoxylated and sulphated), ethoxylated aliphatic alcohol,polyoxyethylene surfactants, carboxylic esters, polyethylene glycolesters, anhydrosorbitol ester and ethoxylated derivatives thereof,glycol esters of fatty acids, carboxylic amides, monoalkanolaminecondensates, polyoxyethylene fatty acid amides, quaternary ammoniumsalts, amines with amide linkages, polyoxyethylene alkyl and alicyclicamines, N,N,N,N tetrakis substituted ethylenediamines, 2-alkyl1-hydroxyethyl 2-imidazolines, N-coco 3-aminopropionic acid/sodium saltN-tallow-3-iminodipropionate disodium salt, N-carboxymethyl-N-dimethylN-9 octadecenyl ammonium hydroxide, N-cocoamidethyln-hydroxyethylglycine sodium salt and the like, polyoxyethylene,sorbitan monolaurate and stearate, Cremophor® (polyethoxylated castoroil), Solutol® (ethylene oxide/12-hydroxy stearic acid), KolliphorHS-15® (Macrogol-15-hydroxystearate), polysorbates, tyloxapol and thelike or mixtures thereof.

Preferably, the ready-to-use or ready-to-dilute compositions comprisesurfactants in an amount from about 0 to about 5 ml of the totalcomposition.

Suitable polymers include, but are not limited to, cellulose derivatives(such as hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, methylcellulose polymers,hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethyleneand carboxymethyl hydroxyethylcellulose or any combination thereof); andacrylics (such as acrylic acid, acrylamide, and maleic anhydridepolymers, copolymers or their mixtures thereof) and the like or mixturesthereof.

Suitable oils include, but are not limited to, castor oil, medium chaintriglycerides (MCTs), mineral oils, vegetable oils, oily fatty acids,oily fatty alcohols, esters of sorbitol, fatty acids, oily sucroseesters, and the like any mixtures thereof. Examples of suitablevegetable oils include cotton seed oil, ground nut oil, corn oil, germoil, olive oil, palm oil, soybean oil, sweet almond oil, sesame oil, andthe like any mixtures thereof. Examples suitable of mineral oils includesilicone oil, petrolatum oil, liquid paraffin and the like or anymixtures thereof. Examples of suitable medium chain triglyceridesinclude coconut oil; hydrogenated oils comprising hydrogenatedcottonseed oil, hydrogenated palm oil, hydrogenated castor oil,hydrogenated soybean oil and the like or any mixtures thereof.

Suitable anti-foaming agents include, but are not limited to, siliconemulsions or sorbitan sesquioleate and the like or mixtures thereof.

Suitable stabilizers to prevent or reduce the deterioration of thecomponents in the compositions of the present invention include, but arenot limited to; metal salts of fatty acids, e.g., MO₂C—R, wherein M ismetal such as lithium, sodium, potassium, magnesium, or calcium, and Ris an alkyl group having from 4-20 carbons, e.g., 4-18 carbons, 4-16carbons, 6-16 carbons or 6-14 carbons. R may include one or moreelements of unsaturation such as an olefinic bond. Exemplary fatty acidsalts include sodium caprylate; sodium N-acetyltryptophanate;antioxidants such as, but are not limited to, glycine, α-tocopherol,α-tocopherol polyethylene glycol succinate (Vitamin E TPGS), ascorbicacid, propyl gallate, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), and the like or mixtures thereof; chelating agents suchas, but are not limited to, salts of ethylenediaminetetraacetic acid(EDTA) such as disodium ethylenediaminetetraacetate (edetate disodium),tetrasodium and trisodium ethylenediaminetetraacetate (Na₄EDTA andNa₃EDTA), hydroxyethylethylenediaminetriacetate (HEDTA),diethylenetriaminepentaacetate (DTPA), nitrilotriacetate (NTA),ethanoldiglycine disodium salt (EDG), diethanolglycine sodium-salt(DEG), and 1,3-propylenediaminetetraacetic acid (PDTA).

Preferably, the ready-to-use or ready-to-dilute compositions willinclude one or more stabilizers in an amount from about 0 to about 500mg.

The ready-to-use and ready-to-dilute compositions can include one ormore tonicity modifies, buffering agents, preservatives and the like.Suitable tonicity modifiers include, but are not limited to, mannitol,sodium chloride, glucose and the like or mixtures thereof. Suitablebuffering agents include, but are not limited to, acetates, phosphates,citrates with suitable cations and the like or mixtures thereof.Suitable preservatives include, but are not limited to, benzalkoniumchloride, benzethonium chloride and cetyl pyridinium chloride, benzylbromide, benzyl alcohol, phenyl mercury nitrate, phenyl mercury acetate,thimerosal, merthiolate, acetate and phenyl mercury borate, polymyxin Bsulphate, chlorhexidine, methyl and propyl parabens, phenylethylalcohol, quaternary ammonium chloride, sodium benzoate, sodiumpropionate, stabilized oxychloro complex, sorbic acid and the like ortheir mixtures thereof.

In a preferred embodiment of the invention, the composition isformulated to have a pH range of 4.5 to 10.0, and more preferably a pHof 7.0 to 9.0. Suitable pH adjusting agents include, but are not limitedto, diethanolamine, triethanolamine, sodium hydroxide, hydrochloricacid, citric acid and monobasic sodium phosphate and the like or theirmixtures thereof.

According to present invention, the ready-to-use or ready-to-dilutecompositions will contain fosaprepitant dimeglumine at concentrationsfrom about 0.5 mg/mL to about 200 mg/mL, preferably from about 1 mg/mLto about 10 mg/mL, more preferably about 1 mg/mL. Alternatively, theready-to-use or ready-to-dilute compositions include from about 50-250mg fosaprepitant dimeglumine. Preferably, the ready-to-use orready-to-dilute compositions comprise 245.3 mg of fosaprepitantdimeglumine of the total composition.

In some embodiments, the compositions can contain from about 50-250 mgfosaprepitant meglumine, from 10-100 mg of at least one salt ofethylenediaminetetraacetic acid, for instance, the disodium salt, from200 mg to 100 g of albumin, and from 3-300 ml of water. The compositionscan also contain additional antioxidants, stabilizers, pH adjusters,tonicity modifiers, buffers and the like. In certain embodiments, theratio of albumin to water can be from 1:100 1:2, from 1:50 to 1:2, from1:25 to 1:2 w/w, from 1:10 to 1:2, from 1:8 to 1:2, from 1:6 to 1:2, orfrom 1:5 to 1:3. In some instance, the ratio of albumin to water isabout 1:4 (w/w). In ready-to-dilute embodiments, the formulations can bediluted with aqueous albumin to give ready-to-use compositions withsimilar ratios of albumin to water. In instances where theready-to-dilute formulation is diluted with vehicles not containingalbumin (e.g., saline, Ringer's solution, and the like), the final ratioof albumin to water (w/w) can be from 1:250 to 1:25, from 1:250 to 1:50,from 1:200 to 1:50, from 1:200 to 1:100, or from 1:175 to 1:125.

The pharmaceutical compositions may be sterilized by methods known inthe art. The compositions may undergo aseptic filtration (e.g., using a0.2 μm disposable pre-sterilized membrane filter). Additionally, thecomposition may be placed into a container (e.g., an intravenoussolution bag, bottle, vial, ampoule, or pre-filled sterile syringe). Thecontainer may have a sterile access port for piercing by a hypodermicinjection needle. In some embodiments, the composition may be filled inone or more pre-sterilized depyrogeneated vials and stopperedaseptically with a pre-sterilized butyl stopper.

According to the present invention, the ready-to-dilute compositions maybe provided in a kit form along with parenterally acceptable diluent.Parenterally acceptable diluents include water for injection, 0.9%saline (normal saline), 0.45% saline (half normal saline), 2.5%dextrose/0.45% saline and albumin solution (5%, 10%, or 25%).

In an embodiment of the invention, there is provided a method fortreating CINV by administering the stable ready-to-use orready-to-dilute pharmaceutical composition of Fosaprepitant dimeglumineusing a suitable dosage level from about 0.001 to 10 mg/kg per day,preferably about 0.005 to 5 mg/kg per day, and especially about 0.05 to5 mg/kg per day. The compositions may be administered on a regimen of 1to 4 times per day, preferably once per day.

For the treatment of certain conditions it may be desirable to use theready-to-use or ready-to-dilute composition of Fosaprepitant dimegluminein conjunction with another pharmacologically active agent. For example,the ready-to-use or ready-to-dilute composition of Fosaprepitantdimeglumine may be presented together with another therapeutic agent asa combined preparation for simultaneous, separate, or sequential use forthe relief of CINV. A preferred combination comprises the ready-to-useor ready-to-dilute composition of Fosaprepitant dimeglumine and acorticosteroid such as Dexamethasone, Triamcinolone, Flunisolide,Budesonide, etc.; and/or an anti-emetic agent, especially 5HT3 receptorantagonists, such as palonosetron, ondansetron, granisetron,tropisetron, decadron, and zatisetron, or GABAB receptor agonists, suchas baclofen. Further, the ready-to-use or ready-to-dilute compositionsof Fosaprepitant dimeglumine may be administered in combination with achemotherapeutic agent such as an alkylating agent, antimetabolite,mitotic inhibitor, or cytotoxic antibiotic, etc.

EXAMPLES

The following examples are set forth below to illustrate the methods andresults according to the disclosed subject matter. These examples arenot intended to be inclusive of all aspects of the subject matterdisclosed herein, but rather to illustrate representative methods,compositions, and results. These examples are not intended to excludeequivalents and variations of the present invention, which are apparentto one skilled in the art.

Efforts have been made to ensure accuracy with respect to numbers (e.g.,amounts, temperature, etc.) but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in ° C. or is at ambient temperature, and pressure is ator near atmospheric. There are numerous variations and combinations ofreaction conditions, e.g., component concentrations, temperatures,pressures, and other reaction ranges and conditions that can be used tooptimize the product purity and yield obtained from the describedprocess. Only reasonable and routine experimentation will be required tooptimize such process conditions.

Stabilized liquid compositions can include excipients according to thefollowing general parameters:

Quantity Ingredients (in total composition) Fosaprepitant dimeglumine50-250 mg Stabilizer 0-500 mg Solubilizer 0-5 mL Vehicle 0-150 mL pHadjusting agent q.s

Example 1: Fosaprepitant Ready-to-Use Composition

Concentration per Ingredients infusion bags Fosaprepitant dimeglumine245.3 mg^(#) Edetate Disodium 56.4 mg Albumin solution, 25% 150 mLSodium hydroxide q.s. to pH 7.2 (NaOH) 0.1N/0.01N Hydrochloric acid(HCl) ^(#)245.3 mg of fosaprepitant dimeglumine is equivalent to 150 mgfosaprepitant free acid

Albumin solution (25%) was mixed with edetate disodium, followed byaddition of fosaprepitant dimeglumine and pH was adjusted, if requiredto 7.2. The solution was aseptically filtered (through 0.2 um filter),filled in suitable container and sealed.

Example 2: Fosaprepitant Ready-to-Dilute Composition

Ingredients Qty/Vial (5 mL) Fosaprepitant dimeglumine 245.3 mg^(#)Edetate Disodium 56.4 mg Albumin solution, 25% 5 mL Sodium hydroxideq.s. to pH 7.2 (NaOH) 0.1N/0.01N Hydrochloric acid (HCl) ^(#)245.3 mg offosaprepitant dimeglumine is equivalent to 150 mg fosaprepitant freeacid

Albumin solution (25%) was mixed with edetate disodium, followed byaddition of fosaprepitant dimeglumine and pH was adjusted, if requiredto 7.2. The solution was aseptically filtered (through 0.2 um filter),filled in suitable container and sealed.

Example 3: Fosaprepitant Ready-to-Dilute Composition

Ingredient Qty/Vial (2 mL) Fosaprepitant dimeglumine 245.3 mg^(#)Glycerin + Ethanol (1:1) q.s. to 2 mL ^(#)245.3 mg of fosaprepitantdimeglumine is equivalent to 150 mg fosaprepitant free acid

Fosaprepitant dimeglumine was dissolved in glycerin and ethanol, and thesolution was aseptically filtered (through 0.2 um filter) and packed insuitable container.

Example 4: Fosaprepitant Ready-to-Dilute Composition

Ingredient Qty/Vial (5 mL) Fosaprepitant dimeglumine 245.3 mg^(#)Edetate Disodium 56.4 mg Albumin solution, 25% 5.0 mL Sodium caprylate482 mg Sodium hydroxide q.s. to pH 7.2 (NaOH) 0.1N/0.01N Hydrochloricacid (HCl) ^(#)245.3 mg of fosaprepitant dimeglumine is equivalent to150 mg fosaprepitant free acid

Albumin solution (25%) was mixed with edetate disodium and sodiumcaprylate, followed by addition of fosaprepitant dimeglumine and pH wasadjusted, if required to 7.2. The solution was aseptically filtered(through 0.2 um filter), filled in suitable container and sealed.

Example 5: Fosaprepitant Ready-to-Dilute Composition

Ingredient Qty/Vial (5 mL) Fosaprepitant dimeglumine 245.3 mg^(#)Albumin 500 mg Edetate Disodium 56.4 mg Water q.s. to 5 mL ^(#)245.3 mgof fosaprepitant dimeglumine is equivalent to 150 mg fosaprepitant freeacid

Albumin was dissolved in water and mixed with edetate disodium, followedby addition of fosaprepitant dimeglumine and pH was adjusted, ifrequired to 7.2. The solution was aseptically filtered (through 0.2 umfilter), filled in suitable container and sealed.

Example 6: Fosaprepitant Ready-to-Dilute Composition

(I) (II) (III) Qty/Vial Qty/Vial Qty/Vial Ingredients (25 mL) (50 mL)(100 mL) Fosaprepitant dimeglumine 245.3 mg^(#) 245.3 mg^(#) 245.3mg^(#) Edetate disodium 56.4 mg 56.4 mg 56.4 mg Albumin solution, 25% 25mL 50 mL 100 mL Sodium hydroxide q.s. to q.s. to q.s. to (NaOH)0.1N/0.01N pH 7.2 pH 7.2 pH 7.2 Hydrochloric acid (HCl) ^(#)245.3 mg offosaprepitant dimeglumine is equivalent to 150 mg fosaprepitant freeacid

Albumin solution (25%) was mixed with edetate disodium, followed byaddition of fosaprepitant dimeglumine and pH was adjusted, if requiredto 7.2. The solution was aseptically filtered (through 0.2 um filter),filled in suitable container and sealed.

Example 7: Fosaprepitant Ready-to-Dilute Composition

Ingredient Qty/Vial (2 mL) Fosaprepitant dimeglumine 245.3 mg^(#)Dimethylacetamide q.s. to 2 mL ^(#)245.3 mg of fosaprepitant dimeglumineis equivalent to 150 mg fosaprepitant free acid

Fosaprepitant dimeglumine was dissolved in dimethylacetamide, and thesolution was aseptically filtered (through 0.2 um filter) and packed insuitable container.

Example 8: Fosaprepitant Ready-to-Dilute Composition

Ingredient Qty/Vial (2 mL) Fosaprepitant dimeglumine 245.3 mg^(#)N-methylpyrrolidone q.s. to 2 mL ^(#)245.3 mg of fosaprepitantdimeglumine is equivalent to 150 mg fosaprepitant free acid

Fosaprepitant dimeglumine was dissolved in N-methylpyrrolidone, and thesolution was aseptically filtered (through 0.2 um filter) and packed insuitable container.

Example 9: Fosaprepitant Ready-to-Dilute Composition

Ingredient Qty/Vial (2 mL) Fosaprepitant dimeglumine 245.3 mg^(#)Propylene glycol 2 gm ^(#)245.3 mg of fosaprepitant dimeglumine isequivalent to 150 mg fosaprepitant free acid

Fosaprepitant dimeglumine was dissolved in propylene glycol, and thesolution was aseptically filtered (through 0.2 um filter) and packed insuitable container.

Example 10: Fosaprepitant Ready-to-Dilute Composition

Ingredient Qty/Vial (2 mL) Fosaprepitant dimeglumine 245.3 mg^(#)Glycerin 0.8 gm Propylene glycol 0.8 gm Ethanol q.s. to 2 mL ^(#)245.3mg of fosaprepitant dimeglumine is equivalent to 150 mg fosaprepitantfree acid

Fosaprepitant dimeglumine was dissolved in glycerine and propyleneglycol, and the solution was aseptically filtered (through 0.2 umfilter) and packed in suitable container.

Example 11: Stability Study

The ready-to-use and ready-to-dilute composition Examples 1 to 4 werestudied for stability of solution with respect to aprepitant content andphysical appearance to evaluate aprepitant precipitation. The resultsare shown in FIG. 1. All the Examples 1 to 4 were clear in physicalappearance indicating no precipitation of aprepitant in the composition.The above mentioned comparison of data confirms the stability offosaprepitant both ready-to-use and ready-to-dilute compositions of thepresent invention.

Example 12: Single Dose Comparative Pharmacokinetic Study in Rat

Method and Material:

Test System Wistar Rat Sex Male Rationale Wistar Rats were used as it iscommonly used rodent species in the pharmacokinetic evaluation of drugs,and acceptable to the regulatory authorities. Source of Animal ResearchFacility, Suven Life Sciences animals Ltd. Total no of 20 animals Age atstudy/ 8 to 12 weeks/250-270 g (±20% variation Body Weight accepted atthe time of dosing) Veterinary Prior to the final assignment to thestudy, Examination rats were subjected to veterinary examination toensure that the selected rats are in a good state of health AnimalAnimals were uniquely identified by tail Identification marking withpermanent marker. Acclimatization On receipt from supplier, the animalswere examined for external signs of ill health prior to acceptance.After health examination, animals were acclimatized for one week undertest conditions. Only animals without any visible signs of illness wereused for the study Grouping and The animals for the experiment wereweighed Randomization and arranged in ascending order of their bodyweights. These stratified body weight of rat were distributed byrandomization procedure using Microsoft excel spreadsheet to all theexperimental groups, such that body weight variation of animals selectedfor the study does not exceed ±20% of the mean body weight. Animal Underisoflurane anesthesia, all animals were catheterization cannulated inright external jugular vein and femoral vein (for intravenous infusion,PE-10 tubing). Rats were surgically implanted with a catheter (externaljugular vein, PE-50 tubing) for repeated withdrawal of blood samples(~0.300 mL volume per predetermined blood collection time). For eachgroup, one standby animal was catheterized as backup. Rats were allowedto recover for minimum of 72 h after cannulation before inclusion instudy and drug administration. General animal health and cannula patencywas confirmed prior to dose administration.

Test Doses:

EMEND® (Fosaprepitant Dimeglumine) for injection

Test formulation 1—Formulation of Example 1

Vehicle and Dose Formulation:

Preparation of 1 mg/mL EMEND for Injection:

Sterile normal saline (0.9% w/v) was used as a vehicle for dilution andinfusion for RLD group.

Step 1: 5 mL 0.9% Sodium Chloride for Injection (normal saline) wasaseptically injected into the vial. The vial was swirled gently avoidingshaking and jetting saline into the vial.

Step 2: A bottle filled with 145 mL of normal saline was preparedaseptically.

Step 3: The entire volume from the vial was aseptically withdrawn andtransferred into the bottle containing 145 mL of normal saline to yielda total volume of 150 mL and a final concentration of 1 mg/1 mL.

Step 4: The bottle was gently inverted 2-3 times.

Test Formulation:

Fosaprepitant Example 1 (1 mg/mL) was administered without any furtherdilutions.

Route of administration: Intravenous slow infusion for 20 minutes.

Intravenous Infusion: Infusion system included a swivel (Instech, USA),tubing (PE50 tubing), syringes and an infusion pump (Pico plus—Harvardapparatus). Glass syringes (Hamilton) were fixed on to the infusionpumps; PE50 tubing was used in connecting the glass syringes at one endand to animal at other end. Each rat was administered 8 mg/kg singledose of Fosaprepitant (EMEND®) or Example 1 by IV infusion for 20 minwith an Infusion volume of 8 mL/kg.

Animal Formulation Infusion Group ID No. Dose strength (mg/mL) volume(EMEND ®)  1-10 8 mg/kg 1 8 mL/kg Example 1 11-20 8 mg/kg 1 8 mL/kg

Blood Collection and Storage of Samples:

Site of blood External Jugular vein (via cannulation) collection Volumeof blood 0.30 mL (approx.) at each time point collected AnticoagulantSodium heparin (Stock: 1000 IU/mL; 10 μL/0.30 mL blood) Blood collection0 (pre-dose), 0.16, 0.33, 0.5, 1, 2, 4, time points 6, 8, 12, 24 hrpost-dose (Total 11 bleedings/rat). Blood 5000 rpm for 5 minutes at 4°C. centrifugation Plasma storage −70° C. until analysis (two aliquots of~0.1 mL each) Note: A pre-dose sample was collected within 1.0 hourprior to dose administration from each rat. Blood samples were kept onice bath till centrifugation and centrifugation was done within 30minutes of collection. On completion of last blood sampling, animalswere sacrificed and carcasses discarded.

Bioanalysis:

Plasma samples from group were analyzed for aprepitant concentrations.Bioanalysis was performed by fit-for-purpose analytical method usingLC-MS/MS.

Pharmacokinetic Data Analysis and Evaluation:

Phoenix® Software, version 6.4, USA was used for studyingPharmacokinetic parameters such as Cmax, Tmax, Kel, T1/2, AUC (0-t), AUC(0-∞), VD, Geometric means, 90 percent Confidence intervals (CI). Dataare presented in FIG. 2.

Example 13: Single Dose Comparative Pharmacokinetic Study in Rat

Method and Material:

Test System Wistar Rat Sex Male Rationale Wistar Rats were used as it iscommonly used rodent species in the pharmacokinetic evaluation of drugs,and acceptable to the regulatory authorities. Source of Animal ResearchFacility, Suven Life Sciences animals Ltd. Total no of 30 animals Age atstudy/ 8 to 12 weeks/220 ± 20 g (±20% variation Body Weight accepted atthe time of dosing) Veterinary Prior to the final assignment to thestudy, Examination rats were subjected to veterinary examination toensure that the selected rats are in a good state of health AnimalAnimals were uniquely identified by tail Identification marking withpermanent marker. Acclimatization On receipt from supplier, the animalswere examined for external signs of ill health prior to acceptance.After health examination, animals were acclimatized for one week undertest conditions. Only animals without any visible signs of illness wereused for the study Grouping and The animals for the experiment wereweighed Randomization and arranged in ascending order of their bodyweights. These stratified body weight of rat were distributed byrandomization procedure using Microsoft excel spreadsheet to all theexperimental groups, such that body weight variation of animals selectedfor the study does not exceed ±20% of the mean body weight. Animal Underisoflurane anesthesia, all animals were catheterization cannulated inright external jugular vein and femoral vein (for intravenous infusion,PE-10 tubing). Rats were surgically implanted with a catheter (externaljugular vein, PE-50 tubing) for repeated withdrawal of blood samples(~0.300 mL volume per predetermined blood collection time). For eachgroup, one standby animal was catheterized as backup. Rats were allowedto recover for minimum of 72 h after cannulation before inclusion instudy and drug administration. General animal health and cannula patencywas confirmed prior to dose administration.

EMEND® (Fosaprepitant Dimeglumine) for injection

Test formulation 2—Example 2

Test formulation 3—Example 3

Vehicle and Dose Formulation:

Sterile normal saline (0.9% w/v) was used as a vehicle for dilution andinfusion.

EMEND® Formulation:

Step 1: 5 mL 0.9% Sodium Chloride for Injection (normal saline) wasaseptically injected into the vial. The vial was swirled gently avoidingshaking and jetting saline into the vial.

Step 2: A bottle filled with 145 mL of normal saline was preparedaseptically.

Step 3: The entire volume from the vial was aseptically withdrawn andtransferred into the bottle containing 145 mL of normal saline to yielda total volume of 150 mL and a final concentration of 1 mg/mL.

Step 4: The bottle was gently inverted 2-3 times.

Test Formulation 2

Step 1: 2 mL formulation was aseptically withdrawn from the vial (75mg/mL strength).

Step 2: 2 mL formulation was aseptically transferred into 148 mL ofnormal saline to yield a total volume of 150 mL and a finalconcentration of 1 mg/mL.

Step 3: The contents were gently mixed before use.

Test Formulation 3

Step 1: 5 mL formulation was aseptically withdrawn from the vial (30mg/mL strength).

Step 2: 5 mL formulation was aseptically transferred into the containercontaining 145 mL of normal saline to yield a total volume of 150 mL anda final concentration of 1 mg/mL.

Step 3: The contents were gently mixed before use.

Route of Administration:

Intravenous slow infusion for 20 minutes.

Intravenous Infusion:

Infusion system included a swivel (Instech, USA), tubing (PE50 tubing),syringes and an infusion pump (Pico plus—Harvard apparatus). Glasssyringes (Hamilton) were fixed on to the infusion pumps; PE50 tubing wasused in connecting the glass syringes at one end and to animal at otherend. Each rat was administered 8 mg/kg single dose of Fosaprepitant(EMEND®) or Fosaprepitant (RTD—2 & 3 formulations) by IV infusion for 20min with an Infusion volume of 8 mL/kg.

Animal Formulation Infusion Group ID No. Dose strength (mg/mL) volumeEMEND ®  1-10 8 mg/kg 1 8 mL/kg Example 2 11-20 8 mg/kg 1 8 mL/kgExample 3 21-30 8 mg/kg 1 8 mL/kg

Blood Collection and Storage of Samples:

Site of blood External Jugular vein (via cannulation) collection Volumeof blood 0.30 mL (approx.) at each time point collected AnticoagulantSodium heparin (Stock: 1000 IU/mL; 10 μL/0.30 mL blood) Blood collection0 (pre-dose), 0.16, 0.33, 0.5, 1, 2, 4, time points 6, 8, 12, 24 hrpost-dose (Total 11 bleedings/rat). Blood 5000 rpm for 5 minutes at 4°C. centrifugation Plasma storage −70° C. until analysis (two aliquots of~0.1 mL each) Note: A pre-dose sample was collected within 1.0 hourprior to dose administration from each rat. Blood samples were kept onice bath till centrifugation and centrifugation was done within 30minutes of collection. On completion of last blood sampling, animalswere sacrificed and carcasses discarded.

Bioanalysis:

Plasma samples from group were analyzed for aprepitant concentrations.Bioanalysis was performed by fit-for-purpose analytical method usingLC-MS/MS.

Pharmacokinetic Data Analysis and Evaluation:

Phoenix® Software, version 6.4, USA was used for studyingPharmacokinetic parameters such as Cmax, Tmax, Kel, T1/2, AUC (0-t), AUC(0-∞), VD, Geometric means, 90 percent Confidence intervals (CI). Dataare presented in FIG. 3.

The compositions and methods of the appended claims are not limited inscope by the specific compositions and methods described herein, whichare intended as illustrations of a few aspects of the claims and anycompositions and methods that are functionally equivalent are intendedto fall within the scope of the claims. Various modifications of thecompositions and methods in addition to those shown and described hereinare intended to fall within the scope of the appended claims. Further,while only certain representative compositions and method stepsdisclosed herein are specifically described, other combinations of thecompositions and method steps also are intended to fall within the scopeof the appended claims, even if not specifically recited. Thus, acombination of steps, elements, components, or constituents may beexplicitly mentioned herein or less, however, other combinations ofsteps, elements, components, and constituents are included, even thoughnot explicitly stated. The term “comprising” and variations thereof asused herein is used synonymously with the term “including” andvariations thereof and are open, non-limiting terms. Although the terms“comprising” and “including” have been used herein to describe variousembodiments, the terms “consisting essentially of” and “consisting of”can be used in place of “comprising” and “including” to provide for morespecific embodiments of the invention and are also disclosed. Other thanin the examples, or where otherwise noted, all numbers expressingquantities of ingredients, reaction conditions, and so forth used in thespecification and claims are to be understood at the very least, and notas an attempt to limit the application of the doctrine of equivalents tothe scope of the claims, to be construed in light of the number ofsignificant digits and ordinary rounding approaches.

What is claimed is:
 1. A liquid composition comprising fosaprepitant or a salt thereof and at least one liquid excipient, wherein after storage at 2-8° C. for at least 1 month, aprepitant is present in an amount concentration of no more than 10%, wherein the composition is ready-to-use or ready-to-dilute.
 2. The liquid composition according to claim 1, wherein the aprepitant concentration is no more than 3%.
 3. The liquid composition according to claim 2, wherein the fosaprepitant is fosaprepitant dimeglumine.
 4. The liquid composition according to claim 1, wherein the liquid excipient comprises aqueous albumin.
 5. The liquid composition according to claim 1, wherein the liquid excipient comprises at least one solubilizer, wherein the solubilizer comprises one or more alcohols, glycols, or aprotic solvents.
 6. The liquid composition according to claim 5, wherein the alcohol is selected from ethanol, octanol, glycofurol or mixtures thereof.
 7. The liquid composition according to claim 5, wherein the glycol is selected from propylene glycol, glycerol, polyethylene glycol or mixtures thereof.
 8. The liquid composition according to claim 5, wherein the aprotic solvent is selected from dimethylacetamide, Isopropyl myristate, dimethylsulphoxide (DMSO), dimethyl isosorbide, methylene chloride, triacetin, diacetin, tributyrin, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral oil, polybutene, silicone fluid, ethyl lactate, N-methyl-2-pyrrolidone, 2-pyrrolidone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethyl formamide, tetrahydrofuran, caprolactam, and 1-dodecylazacyclo-heptan-2-one.
 9. The liquid composition according to claim 5, wherein the solubilizer comprises one or more of ethanol, propylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, or DMSO.
 10. The liquid composition according to claim 1, comprising at least one stabilizer.
 11. The liquid composition according to claim 10, wherein the stabilizer is selected from fatty acid metal salts, antioxidants, and chelating agents.
 12. The liquid composition according to claim 11, wherein the fatty acid metal salt has the formula MO₂C—R, wherein: M is metal selected from lithium, sodium, potassium, magnesium, and calcium; and R is a C₄-C₂₀ alkyl or alkenyl group.
 13. The liquid composition according to claim 12, wherein the fatty acid metal salt is sodium caprylate.
 14. The liquid composition according to claim 11, wherein the antioxidant is selected from glycine, α-tocopherol, a-tocopherol polyethylene glycol succinate, ascorbic acid, propyl gallate, butylated hydroxyanisole, and butylated hydroxytoluene.
 15. The liquid composition according to claim 11, wherein the chelating agent comprises one or more salts of ethylenediaminetetraacetic acid.
 16. The liquid composition according to claim 15, wherein the salt of ethylenediaminetetraacetic acid comprises edetate disodium.
 17. A liquid pharmaceutical composition comprising: a) fosaprepitant dimeglumine in an amount from 50-250 mg; b) at least one salt of ethylenediaminetetraacetic acid in an amount from 10-100 mg; c) albumin in an amount from 250 mg-100 g; and d) water in an amount from 3-300 ml.
 18. The liquid composition according to claim 17, further comprising a fatty acid metal salt in an amount from 100-2,000 mg; wherein the fatty acid metal salt has the formula MO₂C—R, wherein: M is metal selected from lithium, sodium, potassium, magnesium, and calcium; and R is a C₄-C₂₀ alkyl or alkenyl group.
 19. The liquid composition according to claim 18, wherein the fatty acid metal salt comprises sodium caprylate.
 20. A liquid pharmaceutical composition comprising: a) fosaprepitant dimeglumine in an amount from 50-250 mg; and b) at least one solubilizer in an amount from 1-5 ml.
 21. The liquid composition according to claim 20, wherein the solubilizer comprises one or more of ethanol, propylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, or DMSO.
 22. A method of treating chemotherapy-induced nausea and vomiting (CINV), wherein the method comprises administering to a patient a liquid pharmaceutical composition according to claim
 1. 